Acquired immune deficiency syndrome (AIDS) (1) is a disease caused at least in part by the retrovirus human immunodeficiency virus (HIV) (2). AIDS and AIDS-related diseases cause a gradual decline of the immune system and leaves the HIV-infected individuals susceptible to opportunistic infections and to tumor formation that eventually leads to death. Current therapies for these diseases include antiretroviral therapy, which generally involves a cocktail of HIV protease and reverse transcriptase inhibitor drugs. It has been reported that the therapy affords a significant improvement in the general health and quality of life of many HIV-infected individuals. That recovery is also associated with a marked reduction in HIV-associated morbidity and mortality (3). Even so, the HIV protease and reverse transcriptase inhibitor drug cocktail does not cure the patient of the HIV infection nor does it prevent the return of AIDS, once the treatment is stopped. It has been reported that patients who withdraw from the therapy do not benefit from the life-saving treatment. Moreover, for a considerable fraction of AIDS patients this treatment achieves far less than optimal results due to a number of factors, including therapy intolerance, unwanted side effects, other infections, and most notably the development of drug-resistant HIV strains (4). There is a continuing need for additional treatments for AIDS, AIDS-related diseases, and HIV infections.
A member of the Flaviviridae family of positive-sense, single-stranded RNA viruses is the Bovine Viral Diarrhea Virus (BVDV). Infection with this virus brings about a severe mucosal disease in cattle and other ruminants as well as pigs. BVDV cattle infections are marked by nose, mouth and gastrointestinal mucosa ulceration, which cause continuous salivation, nasal discharge, coughing and/or diarrhea. As a result there is a quick virus spread among animals. The virus also causes calves to be still born, become persistently infected, or suffer growth retardation and/or display severe neurological malformations. The economic impact of BVDV is considerable, although it is difficult to precisely estimate its level since certain infections remain undiagnosed or the losses are not recognized as being due to the virus. (see for example, Buckwold et al., Antivirus Research 2003, 60, 1; Finkielsztein et al., 2010, Current Medicinal Chemistry 17, 2933; foregoing publications, and each additional publication cited herein, are incorporated herein by reference). Thus effective therapeutics will be useful for reducing the economic impact of BDVD. Other members of this Flaviviridae family of diseases include West Nile Virus and Dengue Fever.
It has been discovered herein that perhydro pyrrolopyridines are active anti-HIV agents. It has also been discovered herein that perhydro pyrrolopyridines are active against Flaviviridae viruses and related diseases. It has also been discovered herein that perhydro pyrrolopyridines are active anti-BVDV agents. It has also been discovered herein that perhydro pyrrolopyridines are active anti-BVDV agents. It has also been discovered herein that perhydro pyrrolopyridines are active anti-BVDV agents.
In one illustrative embodiment, described herein are substituted perhydro pyrrolopyridines that are useful for the treatment of HIV infections, AIDS, and AIDS-related diseases. In another embodiment, described herein are pharmaceutical compositions comprising the substituted perhydro pyrrolopyridines that are useful for the treatment of HIV infections, AIDS, and AIDS-related diseases. Illustratively, the compositions include one or more carriers, diluents, or excipients, or a combination thereof.
In another embodiment, described herein are methods for treating HIV infections, AIDS, and AIDS-related diseases, where the methods include administering the substituted perhydro pyrrolopyridines and/or the pharmaceutical compositions including the substituted perhydro pyrrolopyridines. In another embodiment, described herein is the use of one or more of the substituted perhydro pyrrolopyridines and/or the pharmaceutical compositions including the substituted perhydro pyrrolopyridines in the manufacture of a medicament for treating a patient or host animal having an HIV infection, AIDS, and AIDS-related diseases.
In another illustrative embodiment, described herein are substituted perhydro pyrrolopyridines that are useful for the treatment of BVDV infections. In another embodiment, described herein are pharmaceutical compositions comprising the substituted perhydro pyrrolopyridines that are useful for the treatment of BVDV infections. Illustratively, the compositions include one or more carriers, diluents, or excipients, or a combination thereof.
In another embodiment, described herein are methods for treating BVDV infections, where the methods include administering the substituted perhydro pyrrolopyridines and/or the pharmaceutical compositions including the substituted perhydro pyrrolopyridines. In another embodiment, described herein is the use of one or more of the substituted perhydro pyrrolopyridines and/or the pharmaceutical compositions including the substituted perhydro pyrrolopyridines in the manufacture of a medicament for treating a patient or host animal having a BVDV infection.
In another illustrative embodiment, described herein are substituted perhydro pyrrolopyridines that are useful for the treatment of West Nile virus infections. In another embodiment, described herein are pharmaceutical compositions comprising the substituted perhydro pyrrolopyridines that are useful for the treatment of West Nile virus infections. Illustratively, the compositions include one or more carriers, diluents, or excipients, or a combination thereof.
In another embodiment, described herein are methods for treating West Nile virus infections, where the methods include administering the substituted perhydro pyrrolopyridines and/or the pharmaceutical compositions including the substituted perhydro pyrrolopyridines. In another embodiment, described herein is the use of one or more of the substituted perhydro pyrrolopyridines and/or the pharmaceutical compositions including the substituted perhydro pyrrolopyridines in the manufacture of a medicament for treating a patient or host animal having a West Nile virus infection.
In another illustrative embodiment, described herein are substituted perhydro pyrrolopyridines that are useful for the treatment of Dengue fever. In another embodiment, described herein are pharmaceutical compositions comprising the substituted perhydro pyrrolopyridines that are useful for the treatment of Dengue fever. Illustratively, the compositions include one or more carriers, diluents, or excipients, or a combination thereof.
In another embodiment, described herein are methods for treating Dengue fever, where the methods include administering the substituted perhydro pyrrolopyridines and/or the pharmaceutical compositions including the substituted perhydro pyrrolopyridines. In another embodiment, described herein is the use of one or more of the substituted perhydro pyrrolopyridines and/or the pharmaceutical compositions including the substituted perhydro pyrrolopyridines in the manufacture of a medicament for treating a patient or host animal having a Dengue fever.